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Science. 2004 Aug 13;305(5686):1010-3.

Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration.

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1
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Abstract

Axonal degeneration is an active program of self-destruction that is observed in many physiological and pathological settings. In Wallerian degeneration slow (wlds) mice, Wallerian degeneration in response to axonal injury is delayed because of a mutation that results in overexpression of a chimeric protein (Wlds) composed of the ubiquitin assembly protein Ufd2a and the nicotinamide adenine dinucleotide (NAD) biosynthetic enzyme Nmnat1. We demonstrate that increased Nmnat activity is responsible for the axon-sparing activity of the Wlds protein. Furthermore, we demonstrate that SIRT1, a mammalian ortholog of Sir2, is the downstream effector of increased Nmnat activity that leads to axonal protection. These findings suggest that novel therapeutic strategies directed at increasing the supply of NAD and/or Sir2 activation may be effective for treatment of diseases characterized by axonopathy and neurodegeneration.

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PMID:
15310905
DOI:
10.1126/science.1098014
[Indexed for MEDLINE]
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